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【结 构 式】 
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【分子编号】25415 【品名】tert-butyl 1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexylcarbamate 【CA登记号】 |
【 分 子 式 】C29H40N4O5 【 分 子 量 】524.66056 【元素组成】C 66.39% H 7.68% N 10.68% O 15.25% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Horner-Emmons reaction of 1-naphthaldehyde (I) with triethyl phosphonoacetate (II) gave naphthyl propenoate (III), which was hydrogenated over Pd/C to afford propanoate (IV), and further reduced to alcohol (V) with LiAlH4. The required naphthyl propylamine (VIII) was then obtained by the sequence of conversion of (V) to mesylate (VI), displacement by NaN3, and reduction of the resulting azide (VII) with LiAlH4. After coupling of (VIII) with N-Boc-L-asparagine N-hydroxysuccinimidyl ester (IX) to give (X), the N-Boc group was deprotected using trifluoroacetic acid in CH2Cl2 to afford amine (XI). Subsequent coupling of (XI) with N-Boc-1-amino-1-cyclohexanecarboxylic acid (XII) by means of DCC and HOBt gave (XIII).
| 【1】 Yao, Z.-J.; King, C.R.; Cao, T.; Kelley, J.; Milne, G.W.; Voigt, J.H.; Burke, T.R. Jr.; Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. J Med Chem 1999, 42, 1, 25. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (III) | 25405 | ethyl (E)-3-(1-naphthyl)-2-propenoate | C15H14O2 | 详情 | 详情 | |
| (IV) | 25406 | ethyl 3-(1-naphthyl)propanoate | C15H16O2 | 详情 | 详情 | |
| (V) | 25407 | 3-(1-naphthyl)-1-propanol | C13H14O | 详情 | 详情 | |
| (VI) | 25408 | 3-(1-naphthyl)propyl methanesulfonate | C14H16O3S | 详情 | 详情 | |
| (VII) | 25409 | 3-(1-naphthyl)propyl azide; 1-(3-azidopropyl)naphthalene | C13H13N3 | 详情 | 详情 | |
| (VIII) | 25410 | 3-(1-naphthyl)-1-propanamine; 3-(1-naphthyl)propylamine | C13H15N | 详情 | 详情 | |
| (IX) | 25411 | tert-butyl (1S)-3-amino-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-3-oxopropylcarbamate | C13H19N3O7 | 详情 | 详情 | |
| (X) | 25412 | tert-butyl (1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropylcarbamate | C22H29N3O4 | 详情 | 详情 | |
| (XI) | 25413 | (2S)-2-amino-N(1)-[3-(1-naphthyl)propyl]butanediamide | C17H21N3O2 | 详情 | 详情 | |
| (XII) | 25414 | 1-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid | C12H21NO4 | 详情 | 详情 | |
| (XIII) | 25415 | tert-butyl 1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexylcarbamate | C29H40N4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The deprotection of (XIII) with trifluoroacetic acid in the presence of triethyl silane provided dipeptide amide (XIV). This was then coupled with the racemic (phosphonomethyl)phenylalanine derivative (XV) using diisopropyl carbodiimide (DIC) and HOBt to yield tripeptide (XVI) as a diastereomeric mixture. The Fmoc group of (XVI) was deprotected with piperidine in acetonitrile, and the resulting amine (XVII) was then coupled with tert-butyl oxalyl chloride (XVIII) to afford (XIX). After chromatographic isolation of the required L,L-diastereoisomer of (XIX), treatment with trifluoroacetic acid cleaved the tert-butyl groups to furnish the title compound.
| 【1】 Yao, Z.-J.; King, C.R.; Cao, T.; Kelley, J.; Milne, G.W.; Voigt, J.H.; Burke, T.R. Jr.; Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. J Med Chem 1999, 42, 1, 25. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 25415 | tert-butyl 1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexylcarbamate | C29H40N4O5 | 详情 | 详情 | |
| (XIV) | 25416 | (2S)-2-[[(1-aminocyclohexyl)carbonyl]amino]-N(1)-[3-(1-naphthyl)propyl]butanediamide | C24H32N4O3 | 详情 | 详情 | |
| (XV) | 25417 | 4-[[di(tert-butoxy)phosphoryl]methyl]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]phenylalanine | C33H40NO7P | 详情 | 详情 | |
| (XVI) | 25418 | di(tert-butyl) 4-(3-[[1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexyl]amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-oxopropyl)benzylphosphonate | C57H70N5O9P | 详情 | 详情 | |
| (XVII) | 25419 | di(tert-butyl) 4-(2-amino-3-[[1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexyl]amino]-3-oxopropyl)benzylphosphonate | C42H60N5O7P | 详情 | 详情 | |
| (XIX) | 25420 | tert-butyl 2-[[(1S)-2-[[1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexyl]amino]-1-(4-[[di(tert-butoxy)phosphoryl]methyl]benzyl)-2-oxoethyl]amino]-2-oxoacetate | C48H68N5O10P | 详情 | 详情 |